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PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.

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cam.issuedOnline2018-09-11
dc.contributor.authorGawden-Bone, Christian M
dc.contributor.authorFrazer, Gordon L
dc.contributor.authorRichard, Arianne C
dc.contributor.authorMa, Claire Y
dc.contributor.authorStrege, Katharina
dc.contributor.authorGriffiths, Gillian M
dc.contributor.orcidGawden-Bone, Christian [0000-0003-0413-3727]
dc.contributor.orcidRichard, Arianne [0000-0002-8708-9997]
dc.contributor.orcidGriffiths, Gillian [0000-0003-0434-5842]
dc.date.accessioned2018-10-03T04:45:44Z
dc.date.available2018-10-03T04:45:44Z
dc.date.issued2018-09-18
dc.description.abstractHow cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kβ across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.
dc.description.sponsorshipWellcome Trust
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.26397
dc.identifier.eissn1097-4180
dc.identifier.issn1074-7613
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283104
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.immuni.2018.08.017
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCTLs
dc.subjectPI(4,5)P2
dc.subjectPIP5K
dc.subjectcytotoxic T lymphocytes
dc.subjectimmunological synapse
dc.subjectphosphatidylinositol 4-phosphate 5-kinase
dc.subjectphosphoinositides phosphatidylinositol 4,5-biphosphate
dc.subjectphospholipids
dc.subjectprimary cilia
dc.subjectsecretion
dc.subjectActins
dc.subjectAnimals
dc.subjectCell Degranulation
dc.subjectCell Line
dc.subjectCell Membrane
dc.subjectCytoplasmic Granules
dc.subjectCytotoxicity, Immunologic
dc.subjectImmunological Synapses
dc.subjectLymphocyte Activation
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectPhosphatidylinositols
dc.subjectPhosphotransferases (Alcohol Group Acceptor)
dc.subjectReceptors, Antigen, T-Cell
dc.subjectSignal Transduction
dc.subjectT-Lymphocytes, Cytotoxic
dc.titlePIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.
dc.typeArticle
dcterms.dateAccepted2018-08-21
prism.endingPage437.e4
prism.issueIdentifier3
prism.publicationDate2018
prism.publicationNameImmunity
prism.startingPage427
prism.volume49
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idWellcome Trust (103930/Z/14/Z)
pubs.funder-project-idMedical Research Council (MR/P014178/1)
pubs.funder-project-idAddenbrooke's Charitable Trust (ACT) (Minute 23/17 A (ii))
pubs.funder-project-idWellcome Trust (075880/Z/04/A)
pubs.funder-project-idIsaac Newton Trust (14.38(c))
rioxxterms.licenseref.startdate2018-09-11
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.immuni.2018.08.017

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